纤维蛋白原与凝血酶药物混悬液的制备方法研究

Preparation Method Study of Fibrinogen and Thrombin Drug Suspension

目的使用不同方法制备纤维蛋白原与凝血酶的药物混悬液,优选制备工艺并初步评价该混悬液的制剂性质。方法无水乙醇作为分散剂,采用研磨筛分法、胶体磨研磨法和高速分散均质法制备纤维蛋白原、凝血酶与氯化钙的药物混悬液,考察制得混悬液的粒径分布、沉降体积比、温度、pH、黏度,检测混悬后纤维蛋白原药物的凝固活力,计算药物回收率,并综合以上考察项对该混悬工艺进行评估。结果研磨筛分法回收率低于50%,胶体磨研磨法易引入杂质,最终优选高速分散均质法。研究确定分散机单次处理程序为转速15.0×10^(3)r·min^(-1),粉碎时间2 min,共循环10次,所得混悬液粒径为6.46~161.13μm,中位粒径﹤50μm,5 min沉降体积比高于90%,药液处理前后温度变化控制在5℃之内,pH值范围为7.5~8.5,黏度值范围为20~35 mPa·s,药物回收率高于90%,且纤维蛋白原药物活性符合《中国药典》(2020年版)标准。结论高速分散均质法是1种可行的纤维蛋白原与凝血酶药物混悬液制备方法,所得混悬液的生物活性良好、可用于纤维蛋白止血贴的制备。

OBJECTIVE To select an optimal preparation method of fibrinogen and thrombin drug suspension,and preliminary evaluate the formulation property of the prepared suspension.METHODS Absolute ethanol was used as the dispersant.The drug suspension of fibrinogen,thrombin and calcium chloride was prepared by grinding and sieving method,colloid mill method and high⁃speed dispersion homogenization method,respectively.Particle size distribution,sedimentation coefficient,suspension temperature,pH and viscosity of the prepared suspension were investigated,while the coagulation activity of fibrinogen after suspension and the drug recovery rate during the preparation were also studied for a thorough evaluation of the preparation method.RESULTS The recovery rate of grinding and sieving method was less than 50%;the colloid grinding method tended to introduce impurities;the high⁃speed dispersion homogenization method was proved to be optimal.The determined treatment program was as followed:rotation speed of 15.0×10^(3)r·min^(-1),crushing time of 2 min,10 times of circulation.The particle size range of the obtained suspension was 6.46-161.13μm;the median particle size was less than 50μm;the 5 min sedimentation volume ratio was higher than 90%;temperature change before and after treatment was within 5℃;the pH was 7.5-8.5;the viscosity was 20-35 mPa·s;the drug recovery rate was higher than 90%;the fibrinogen drug activity met the standards of the Chinese Pharmacopoeia(2020 edition).CONCLUSION The high⁃speed dispersion and homogenization is a feasible method for the preparation of fibrinogen and thrombin drug suspension;the obtained suspension exhibits good biological activity and utility in fibrin hemostatic patch preparation.